The role of fat-storing cells and of the acute phase response in rat liver fibrogenesis

Abstract

Fat-storing cells (FSC) are the main producers of extracellular matrix components (EMC) in the liver. FSC are heterogeneous with regard to vitamin A content and expression of desmin, vimentin and {dollar}\alpha{dollar}-actin. To determine whether FSC are heterogeneous with regard to proliferation and expression of cytokines and EMC, we developed FSC lines from normal (NFSC) and CCl{dollar}\sb4{dollar}-cirrhotic (CFSC) livers. We determined proliferation index (PI) and expression of {dollar}\alpha{dollar}1(I), {dollar}\alpha{dollar}1(III), {dollar}\alpha{dollar}1(IV) procollagens, laminin, fibronectin, interleukin-6 (IL-6) and transforming growth factor-{dollar}\beta{dollar}1 (TGF-{dollar}\beta{dollar}) mRNAs. CFSC produce twice as much collagen, and 1.5 times more fibronectin. NFSC but not CFSC produce IL-6. CFSC were cloned by the limiting dilution method. The clones obtained are heterogeneous with regard to PI and expression of mRNAs coding for EMC and cytokines. Two CFSC-derived clones expressed IL-6 mRNA.;IL-6 is one of the main cytokines produced during the acute phase response (APR). In some instances, this response may exacerbate liver fibrogenesis. We determined whether recombinant IL-6 (rIL-6) induced collagen gene expression in FSC. rIL-6 stimulated transcription of the {dollar}\alpha{dollar}1(I) procollagen (COL-I) gene in FSC. This induction required de novo protein synthesis. rIL-6 also stimulated fibronectin and TGF-{dollar}\beta{dollar} mRNA expression. CFSC-derived clones were heterogeneous in their response to rIL-6. Clones with low basal levels of COL-I mRNA were highly responsive to this cytokine. In contrast, clones with high basal expression of COL-I mRNA did not respond to IL-6.;To determine whether these findings had any relevance in vivo, we induced an APR with turpentine in rats and obtained mRNA from their livers. mRNA levels for COL-I were increased in those animals. Colchicine, a drug used in the treatment of liver cirrhosis, prevented this turpentine-induced effect. Our results suggest that FSC are heterogeneous with regard to EMC and cytokine production as well as in their response to cytokines. We speculate that FSC heterogeneity may be a determinant factor in development of cirrhosis. We conclude that the APR in general, and IL-6 in particular, play an important role in collagen deposition in liver fibrogenesis.